Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed by diverse cell types that play an important role in both innate and adaptive immunity. TLRs are type I membrane proteins with distinct sub-cellular localization and recognize a range of highly conserved molecular structures present on microbial pathogens termed pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs) (Beutler 2009; Kawai and Akira 2011). To date, 13 TLR isoforms have been identified in mammals, 10 in humans, and the individual receptors have been characterized to recognize specific ligands. Ligands can broadly be categorized into three groups; lipids and lipopeptides, proteins and nucleic acids. Lipid-based bacterial cell wall components such as lipoproteins are recognized by TLR1, 2, 6 and lipopolysaccharides by TLR4. Microbial proteins such as flagellin are recognized by TLR5. Exogenous nucleic acids in the form of CpG DNA are recognized by TLR9 and single or double stranded RNA are recognized by TLR7 and TLR3, respectively. Certain TLRs bind not only to microbial products but also recognize ‘self’ ligands known as damage-associated molecular patterns (DAMPs), which are proteins or nucleic acids released from stressed, damaged or dying cells and tissues. Cells of the innate immune system respond to PAMPs/MAMPs and DAMPs by producing proinflammatory cytokines and chemokines that signal for the clearance of the pathogens and damaged-self. Upon engagement with specific ligands, TLR activation leads to the activation of transcription factors such as nuclear factor kappa B (NF)-B, activating protein-1 (AP-1) and interferon regulatory factors (IRFs) through several adaptor molecules including myeloid differentiation primary response gene 88 MyD88, Toll-interleukin 1 receptor (TIR) domain containing adaptor protein TIRAP and TIR-domain containing adaptor inducing interferon-beta TRIF, to regulate cytokine expression. The production and secretion of cytokines such as interferons (IFNs), TNF-α and interleukins, as well as co-stimulatory molecules, contribute to the death and clearance of the pathogenic invasion and dead cells. In addition to TLRs, the innate immune system comprises other germline-encoded PRRs families, which include the Nod-like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and cytosolic DNA sensors (CDSs). The recognition of exogenous nucleic acids in the cytoplasm of cells by CDSs and RLRs has been recently understood to play a major role in triggering innate immune responses (Keating et al. 2011). Stimulation of multiple receptors of the innate immune system can effectively drive a more specific adaptive immune response, which is responsible for developing antigen-specific memory. Novel therapeutic strategies attempt to harness receptors of the innate immune system to systematically shape an immune response to fight infections, immune disorders and diseases such as cancer.
Targeting PRRs and more particularly TLRs and cytosolic nucleic sensors for therapeutic purposes is a growing interest in the prevention and treatment of infections, immune-diseases and cancers.